Platelet aggregation constitutes the initial hemostatic response to curtail bleeding induced by vascular injury. However, pathological extension of this normal hemostatic process can lead to thrombus formation. The final, common pathway in platelet aggregation is the binding of fibrinogen to activated, exposed platelet glycoprotein IIb/IIIa (GPIIb/IIIa). Agents which interrupt binding of fibrinogen to GPIIb/IIIa, therefore, inhibit platelet aggregation. These agents are, therefore, useful in treating platelet-mediated thrombotic disorders such as arterial and venous thrombosis, acute myocardial infarction, unstable angina, reocclusion following thrombolytic therapy and angioplasty, inflammation, and a variety of vaso-occlusive disorders. The fibrinogen receptor (GPIIb/IIIa) is activated by stimuli such as ADP, collagen, and thrombin exposing binding domains to two different peptide regions of fibrinogen: alpha-chain Arg-Gly-Asp (RGD) and gamma-chain His-His-Leu-Gly-Gly-Ala-Lys-Gln-Ala-Gly-Asp-Val (HHLGGAKQAGDV, .gamma.400-411). Since these peptide fragments themselves have been shown to inhibit fibrinogen binding to GPIIb/IIIa, a mimetic of these fragments would also serve as an antagonist. In fact, prior to this invention, potent RGD-based antagonists have been revealed which inhibit both fibrinogen binding to GPIIb/IIIa and platelet aggregation e.g., Ro-438857 (L. Alig, J. Med. Chem. 1992, 35, 4393) has an IC.sub.50 of 0.094 .mu.M against in vitro thrombin-induced platelet aggregation. Some of these agents have also shown in vivo efficacy as antithrombotic agents and, in some cases, have been used in conjunction with fibrinolytic therapy e.g., t-PA or streptokinase, as well (J. A. Zablocki, Current Pharmaceutical Design 1995, 1, 533).
The glycolamide ester compounds of the present invention are orally-active GPIIb/IIIa antagonists which exhibit improved oral absorption and in vivo activity over their carboxylic acid congeners. As demonstrated by the results of the pharmacological studies described hereinafter, the compounds show the ability to block fibrinogen binding to isolated GPIIb/IIa (IC.sub.50 's of ca. 0.0005-0.01 .mu.M), inhibit platelet aggregation in vitro in the presence of a variety of platelet stimuli (IC.sub.50 's of ca. 0.1-1.0 .mu.M vs. thrombin), and furthermore, inhibit ex vivo platelet aggregation in animal models. Additionally, these agents exhibit efficacy in animal thrombosis models as their progenitors had shown ("Nipecotic Acid Derivatives As Antithrombotic Compounds," application Ser. No. 08-213772, filed Mar. 16, 1994 and "Carboxamide Derivatives of Pyrrolidine, Piperidine, and Hexahydroazepine for the Treatment of Thrombosis Disorders," application Ser. No. 60-016675, filed May 1, 1996). The compounds of the present invention are carboxylic acid glycolamide esters which show efficacy as antithrombotic agents by virtue of their ability to prevent platelet aggregation. Additionally, because the compounds of this invention inhibit integrin-mediated cell-cell or cell-matrix adhesion, they may be useful against inflammation, bone resorption, tumor cell metastasis, etc. (D. Cox, Drug News & Perspectives 1995, 8,197).